Uses of DPP-IV inhibitors

ABSTRACT

The specification describes the use of selected DPP IV inhibitors for the treatment of physiological functional disorders and for reducing the risk of the occurrence of such functional disorders in at-risk patient groups. In addition, the use of the above-mentioned DPP IV inhibitors in conjunction with other active substances is described, by means of which improved treatment outcomes can be achieved. These applications may be used to prepare corresponding medicaments.

This Application claims priority of EP 06 009 203, which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The specification describes the use of selected DPP IV inhibitors forthe treatment of physiological functional disorders and for reducing therisk of the occurrence of such functional disorders in at-risk patientgroups. In addition, the use of the above-mentioned DPP IV inhibitors inconjunction with other active substances is described, by means of whichimproved treatment outcomes can be achieved. These applications may beused to prepare corresponding medicaments.

2. Description of the Prior Art

The enzyme DPP-IV, also known by the name CD26, is a serine proteasewhich promotes the cleaving of dipeptides in proteins with a proline oralanine group at the N-terminal end. DPP-IV inhibitors thereby influencethe plasma level of bioactive peptides including the peptide GLP-1 andare highly promising molecules for the treatment of diabetes mellitus.

Type 1 diabetes mellitus, which occurs mainly in juveniles under 30years of age, is categorised as an autoimmune disease. With acorresponding genetic disposition and under the influence of variousfactors, insulitis occurs, followed by destruction of the B-cells, sothat the pancreas is no longer able to produce much, if any, insulin.

Type 2 diabetes mellitus is not categorised as an autoimmune disease andmanifests itself in a fasting blood sugar level exceeding 125 mg ofglucose per dl of plasma; the measurement of blood glucose values is astandard procedure in routine medical analysis. Prediabetes is suspectedif the fasting blood sugar level exceeds the maximum normal level of 99mg of glucose per dl of plasma but does not exceed the threshold of 125mg of glucose per dl of plasma, which is relevant for diabetes. This isalso referred to as pathological fasting glucose (impaired fastingglucose). Another indication of prediabetes is a disrupted glucosetolerance, i.e. a blood sugar level of 140-199 mg of glucose per dl ofplasma 2 hours after taking 75 mg of glucose on an empty stomach withinthe scope of an oral glucose tolerance test.

If a glucose tolerance test is carried out, the blood sugar level of adiabetic will be in excess of 199 mg of glucose per dl of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach. In a glucosetolerance test 75 g of glucose are administered orally to the patientbeing tested after 10-12 hours of fasting and the blood sugar level isrecorded immediately before taking the glucose and 1 and 2 hours aftertaking it. In a healthy subject the blood sugar level will be between 60and 99 mg per dl of plasma before taking the glucose, less than 200 mgper dl 1 hour after taking it and less than 140 mg per dl after 2 hours.If after 2 hours the value is between 140 and 199 mg this is regarded asabnormal glucose tolerance or in some cases glucose intolerance.

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1c level is not sufficient in all diabetics to bringthem into the desired target range of <6.5% and preferably <6% HbA1c.

If insulin resistance can be detected this is a particularly strongindication of the presence of the complex metabolic disorder ofprediabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as another person.The most certain method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. Another method of measurement is themathematical HOMA model. The insulin resistance is calculated by meansof the fasting plasma glucose and the fasting insulin concentration. Inthis method it is not possible to distinguish between hepatic andperipheral insulin resistance. These processes are not really suitablefor evaluating insulin resistance in daily practice. As a rule, otherparameters are used in everyday clinical practice to assess insulinresistance. Preferably, the patient's triglyceride concentration isused, for example, as increased triglyceride levels correlatesignificantly with the presence of insulin resistance.

To simply somewhat, in practice it is assumed that people areinsulin-resistant if they have at least 2 of the followingcharacteristics:

-   1) overweight or obesity-   2) high blood pressure-   3) dyslipidaemia (an altered content of total lipids in the blood)-   4) at least one close relative in whom abnormal glucose tolerance or    type 2 diabetes has been diagnosed.

Overweight means in this instance that the Body Mass Index (BMI) isbetween 25 and 30 kg/m², the BMI being the quotient of the body weightin kg and the square of the height in metres. In manifest obesity theBMI is 30 kg/m² or more.

It is immediately apparent, from the above definition of insulinresistance, that hypotensive agents are suitable and indicated fortreating it if, among other things, high blood pressure is found in thepatient.

A similar indication of prediabetes is if the conditions for metabolicsyndrome are met, the main feature of which is insulin resistance.According to the ATP IHINCEP Guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) in theJournal of the American Medical Association 285:2486-2497, 2001)metabolic syndrome is present if a patient has at least 3 of thefollowing characteristics:

-   1) Abdominal obesity, defined as a waist measurement of >40 inches    or 102 cm in men and >35 inches or 94 cm in women-   2) Triglyceride levels>150 mg/dl-   3) HDL-cholesterol levels<40 mg/dl in men-   4) High blood pressure>130/>85 mm Hg-   5) Fasting blood sugar of >110 mg/dl

This definition of metabolic syndrome immediately shows thathypotensives are suitable for treating it if the patient is found tohave high blood pressure, among other things.

A triglyceride blood level of more than 150 mg/dl also indicates thepresence of pre-diabetes. This suspicion is confirmed by a low bloodlevel for HDL cholesterol. In women, levels below 55 mg per dl of plasmaare regarded as too low while in men levels below 45 mg per dl of plasmaare regarded as too low. Triglycerides and HDL cholesterol in the bloodcan also be determined by standard methods in medical analysis and aredescribed for example in Thomas L (Editor): “Labor und Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000. A suspicion ofprediabetes is further confirmed if the fasting blood sugar levels alsoexceed 99 mg of glucose per dl of plasma.

The term gestational diabetes (diabetes of pregnancy) denotes a form ofthe sugar disease which develops during pregnancy and usually ceasesagain immediately after the birth. Gestational diabetes is diagnosed bya screening test which is carried out between the 24th and 28th weeks ofpregnancy. It is usually a simple test in which the blood sugar level ismeasured one hour after the administration of 50 g of glucose solution.If this 1 h level is above 140 mg/dl, gestational diabetes is suspected.Final confirmation may be obtained by a standard glucose tolerance testwith 75 g of glucose.

Hyperglycaemia describes a functional disorder in which an excessivelyhigh glucose level is measured in the blood, either in the fasting state(increased glucose level of 100-125 mg/dl or diabetic-hyperglycaemiclevel of >125 mg/dl compared with the normal level of <100 mg/dl,) or innon-fasting state (elevated glucose level of >180 mg/dl).

By adrenergic postprandial syndrome (reactive hypoglycaemia) theclinician means a functional disorder in which a disproportionately highinsulin level leads to a drop in the blood sugar level (hypoglycaemia)caused by an imbalance between rapidly digested carbohydrates and a highinsulin level persisting after a meal.

The term diabetic foot refers to lesions on the foot caused by diabetesmellitus, the primary cause of which is a polyneuropathy that can be putdown to inadequate metabolic control. A diabetic foot is diagnosed bythe occurrence of typical lesions (e.g. ulcers) in an existing case ofdiabetes mellitus.

The term diabetes-associated ulcer refers to an ulcerous inflammatoryskin defect in a patient with diabetes mellitus. A diabetes-associatedulcer is diagnosed by typical anamnesis and physical examination (e.g.inspection of the foot).

The term diabetic hyperlipidaemia is used if a patient with diabetesmellitus suffers an increase in total cholesterol or, more typically indiabetic hyperlipidaemia, an increase in the plasma triglycerides, withor without a reduction in HDL cholesterol.

The term diabetic dyslipidaemia is used if the total cholesterol is notraised but the distribution of HDL- and LDL-cholesterol is altered, i.e.the patient's HDL cholesterol level is too low (e.g. <55 mg/dl for womenand <45 mg/dl for men).

The term heart failure is used if either subjective symptoms orobjective findings indicate an inability of the heart to achieve thenecessary ejection output. Subjective symptoms may be e.g. difficultybreathing under stress or at rest. Objective findings include a reducedejection output of the heart according to ultrasound (reduced ejectionvolume), congestion of the lungs according to X-ray, and/or reducedwalking distances.

DETAILED DESCRIPTION OF THE INVENTION

Some selected DPP IV inhibitors are particularly suitable for thepreparation of a medicament for the therapeutic treatment of patientswho have been diagnosed with a medical or physiological functionaldisorder selected from among pre-diabetes, glucose intolerance (impairedglucose tolerance), pathological fasting glucose (impaired fastingglucose), diabetic foot, diabetes-associated ulcer, diabetichyperlipidaemia, diabetic dyslipidaemia, newly diagnosed type 1 diabetes(to maintain a residual secretion of insulin from the pancreas),gestational diabetes (diabetes of pregnancy), hyperglycaemia, adrenergicpostprandial syndrome (reactive hypoglycaemia) or heart failure.

These medicaments may also be used to reduce the risk that in spite oftreatment the patient will suffer an impaired glucose metabolism, anelevated HbA1c value, an impaired fasting glucose value, manifest type 2diabetes, a diabetic foot, a diabetes-associated ulcer, diabetichyperlipidaemia or diabetic dyslipidaemia, and that in spite of thetherapy insulin treatment will become necessary or macrovascularcomplications will occur.

Examples of macrovascular complications of this kind are myocardialinfarct, acute coronary syndrome, unstable angina pectoris, stableangina pectoris, haemorrhagic or ischaemic stroke, peripheral arterialocclusive disease, cardiomyopathy, left heart insufficiency, right heartinsufficiency, global heart insufficiency, heart rhythm disorders andvascular restenosis. These macrovascular complications are known to theskilled man and described in detail in the standard textbooks.

In addition the substances are suitable for enhancing the vitality andsecretion capacity of cells after the transplanting of islets ofLangerhans or beta cells, and thereby ensuring a favourable outcomeafter transplantation. The substances may also be used during theisolation and transplantation phase of islets of Langerhans or betacells, by adding the specified substances to the conventional isolationor storage medium in a suitable concentration of 1 nmol/l to 1 μmol/l,preferably in a concentration of 1 nmol/l to 100 nmol/l. This results inan improvement in the quality of the material to be transplanted. Animprovement in quality is obtained particularly in combination withadded amounts of GLP-1 (glucagon like peptide 1), preferably in aconcentration of 1-100 nmol/l. Corresponding isolation or storage mediaand corresponding methods of enhancing the vitality and secretioncapacity of islets of Langerhans or beta cells by the addition of DPP IVinhibitors to the media used are a further object of the invention.

Finally, the above-mentioned inhibitors are suitable for the treatmentof various forms of arthritis, but particularly rheumatoid arthritis.

DPP IV inhibitors selected according to the present invention can bedescribed by formula (I)

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino.

Particularly preferred DPP IV inhibitors are the following compounds andthe therapeutically active salts thereof:

-   -   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine        (cf. WO 2004/018468, Example 2(142):

-   -   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2004/018468, Example 2(252)):

-   -   1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2004/018468, Example 2(80)):

-   -   2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-on        (cf. WO 2004/050658, Example 136):

-   -   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine        (cf. WO 2006/029769, Example 2(1)):

-   -   1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2005/085246, Example 1 (30)):

-   -   1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2005/085246, Example 1(39)):

-   -   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine        (cf. WO 2006/029769, Example 2(4)):

-   -   1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2005/085246, Example 1(52)):

-   -   1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2005/085246, Example 1(81)):

-   -   1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2005/085246, Example 1(82)):

-   -   1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine        (cf. WO 2005/085246, Example 1(83)):

These DPP IV inhibitors are distinguished from structurally comparableDPP IV inhibitors, as they combine exceptional potency and along-lasting effect with favourable pharmacological properties, receptorselectivity and a favourable side-effect profile or bring aboutunexpected therapeutic advantages or improvements when combined withother pharmaceutical active substances. Their preparation is disclosedin the publications mentioned.

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP IVinhibitor is combined with an active substance selected from among theother antidiabetic substances, especially active substances that lowerthe blood sugar level or the lipid level in the blood, raise the HDLlevel in the blood, lower blood pressure or are indicated in thetreatment of atherosclerosis or obesity.

The dosage required of the DPP IV inhibitors when administeredintravenously is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and whenadministered orally 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg, ineach case 1 to 4 times a day. For this purpose the compounds, optionallyin combination with another active substance, may be formulated togetherwith one or more inert conventional carriers and/or diluents, e.g. withmaize starch, lactose, glucose, microcrystalline cellulose, magnesiumstearate, polyvinylpyrrolidone, citric acid, tartaric acid, water,water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol,propyleneglycol, cetylstearylalcohol, carboxymethylcellulose or fattysubstances such as hard fat or suitable mixtures thereof, to formconventional galenic preparations such as tablets, coated tablets,capsules, powders, suspensions or suppositories.

The DPP IV inhibitors according to the invention are thus prepared bythe skilled man using permitted formulation excipients as described inthe prior art. Examples of such excipients are diluents, binders,carriers, fillers, lubricants, flow agents, crystallisation retardants,disintegrants, solubilisers, colourings, pH regulators, surfactants andemulsifiers.

Examples of suitable diluents include cellulose powder, calcium hydrogenphosphate, erythritol, (low-substituted) hydroxypropylcellulose,mannitol, pregelatinised starch or xylitol.

Examples of suitable binders include copolymers of vinylpyrrolidone withother vinyl derivatives (copovidone), hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC) polyvinylpyrrolidone (povidone),pregelatinised starch, or low-substituted hydroxypropylcellulose.

Examples of suitable lubricants include talc, polyethyleneglycol,calcium behenate, calcium stearate, hydrogenated castor oil or magnesiumstearate.

Examples of suitable disintegrants include maize starch or crospovidone.Suitable methods of preparing pharmaceutical formulations of the DPP IVinhibitors according to the invention are

-   -   Direct tabletting of the active substance in powder mixtures        with suitable tabletting excipients;    -   Granulation with suitable excipients and subsequent mixing with        suitable excipients and subsequent tabletting as well as film        coating; or    -   packing of powder mixtures or granules into capsules.

Suitable granulation methods are

-   -   wet granulation in the intensive mixer followed by fluidised bed        drying;    -   one-pot granulation;    -   fluidised bed granulation; or    -   dry granulation (e.g. by roller compaction) with suitable        excipients and subsequent tabletting or packing into capsules.

The DPP IV inhibitors mentioned above may also be used in conjunctionwith other active substances, by means of which improved treatmentresults can be obtained. Such a combined treatment may be given as afree combination of the substances or in the form of a fixedcombination, for example in a tablet or capsule. Pharmaceuticalformulations of the combination partner needed for this may either beobtained commercially as pharmaceutical compositions or may beformulated by the skilled man using conventional methods. The activesubstances which may be obtained commercially as pharmaceuticalcompositions are described in numerous places in the prior art, forexample in the list of drugs that appears annually, the “Rote Liste®” ofthe federal association of the pharmaceutical industry, or in theannually updated compilation of manufacturers' information onprescription drugs known as the “Physicians' Desk Reference”.

Examples of antidiabetic combination partners are metformin;sulphonylureas such as glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone;PPAR gamma modulators such as metaglidases; PPAR-gamma agonists such asGI 262570; PPAR-gamma antagonists; PPAR-gamma/alpha modulators such astesaglitazar, muraglitazar and KRP297; PPAR-gamma/alpha/deltamodulators; AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT)inhibitors; pancreatic beta cell GCRP agonists such asSMT3-receptor-agonists and GPR119; 11β-HSD-inhibitors; FGF19 agonists oranalogues; alpha-glucosidase blockers such as acarbose, voglibose andmiglitol; alpha2-antagonists; insulin and insulin analogues such ashuman insulin, insulin lispro, insulin glusilin, r-DNA-insulinaspart,NPH insulin, insulin detemir, insulin zinc suspension and insulinglargin; Gastric inhibitory Peptide (GIP); pramlintide; amylin or GLP-1and GLP-1 analogues such as Exendin-4; SGLT2-inhibitors such asKGT-1251; inhibitors of protein tyrosine-phosphatase; inhibitors ofglucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogenphosphorylase modulators; glucagon receptor antagonists;phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvatedehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976);glucokinase/regulatory protein modulators incl. glucokinase activators;glycogen synthase kinase inhibitors; inhibitors of theSH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKKinhibitors such as high-dose salicylate; JNK1 inhibitors; protein kinaseC-theta inhibitors; beta 3 agonists such as ritobegron, YM 178,solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825;aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat,epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2inhibitors; KV 1.3 channel inhibitors; GPR40 modulators; SCD-1inhibitors; CCR-2 antagonists; and other DPP IV inhibitors.

Examples of 11β-HSD1-inhibitors are described in WO 2007/013929, WO2007/007688, WO 2007/003521, WO 2006/138508, WO 2006/135795, WO2006/135667, WO 2006/134481, WO 2006/134467, WO 2006/132436, WO2006/132197, WO 2006/113261, WO 2006/106423, WO 2006/106052, WO2006/105127, WO 2006/104280, WO 2006/100502, WO 2006/097337, WO2006/095822, WO 2006/094633, WO 2006/080533, WO 2006/074330, WO2006/074244, WO 2006/068992, WO 2006/068991, WO 2006/068199, WO2006/066109, WO 2006/055752, WO 2006/053024, WO 2006/051662, WO2006/050908, WO 2006/049952, WO 2006/048750, WO 2006/048331, WO2006/048330, WO 2006/040329, WO 2006/037501, WO 2006/030805, WO2006/030804, WO 2006/017542, WO 2006/024628, WO 2006/024627, WO2006/020598, WO 2006/010546, WO 2006/002349, WO 2006/002350, WO2006/012173, WO 2006/012227, WO 2006/012226, WO 2006/000371, WO2005/118538, WO 2005/116002, WO 2005/110992, WO 2005/110980, WO2005/108359, WO 2005/108361, WO 2005/108360, WO 2005/108368, WO2005/103023, WO 2005/097764, WO 2005/097759, WO 2005/095350, WO2005/075471, WO 2005/063247, WO 2005/060963, WO 2005/047250, WO2005/046685, WO 2005/044192, WO 2005/042513, WO 2005/016877, WO2004/113310, WO 2004/106294, WO 2004/103980, WO 2004/089896, WO2004/089380, WO 2004/089471, WO 2004/089470, WO 2004/089367, WO2005/073200, WO 2004/065351, WO 2004/058741, WO 2004/056745, WO2004/056744, WO 2004/041264, WO 2004/037251, WO 2004/033427, WO2004/011410, WO 2003/104208, WO 2003/104207, WO 2003/065983, WO2003/059267, WO 2003/044009, WO 2003/044000, WO 2003/043999, WO2002/076435, WO 2001/090094, WO 2001/090093, WO 2001/090092, WO2001/090091, WO 2001/090090, US 2007/049632, US 2006/148871, US2006/025445, US 2006/004049, US 2005/277647, US 2005/261302, US2005/245534, US 2005/245532, US 2005/245533 and JP 2005/170939. Theforegoing references are hereby incorporated by reference in theirentireties. A representative example of an 11β-HSD1-inhibitor is thecompound:

and the salts thereof.

Examples of glycogen phosphorylase modulators are described in WO2006/126695, WO 2006/082401, WO 2006/082400, WO 2006/059165, WO2006/059164, WO 2006/059163, WO 2006/056815, WO 2006/055463, WO2006/055462, WO 2006/055435, WO 2006/053274, WO 2006/052722, WO2005/085245, WO 2005/085194, WO 2005/073231, WO 2005/073230, WO2005/073229, WO 2005/067932, WO 2005/020987, WO 2005/020986, WO2005/020985, WO 2005/019172, WO 2005/018637, WO 2005/013981, WO2005/013975, WO 2005/012244, WO 2004/113345, WO 2004/104001, WO2004/096768, WO 2004/092158, WO 2004/078743, WO 2004/072060, WO2004/065356, WO 2004/041780, WO 2004/037233, WO 2004/033416, WO2004/007455, WO 2004/007437, WO 2003/104188, WO 2003/091213, WO2003/084923, WO 2003/084922, WO 2003/074532, WO 2003/074531, WO2003/074517, WO 2003/074513, WO 2003/074485, WO 2003/074484, WO2003/072570, WO 2003/059910, WO 2003/037864, WO 2002/096864, WO2002/020530, WO 2001/094300, WO 2000/123347, WO 1996/39384, WO1996/39385, EP 1391460, EP 1136071, EP 1125580, EP 1088824, EP 0978279,JP 2004196702, US 2004/002495, US 2003/195243, and U.S. Pat. No.5,998,463. The foregoing references are hereby incorporated by referencein their entireties.

Examples of glucokinase-activators are described in WO 2007/017649, WO2007/007910, WO 2007/007886, WO 2007/007042, WO 2007/007041, WO2007/007040, WO 2007/006814, WO 2007/006761, WO 2007/006760, WO2006/125972, WO 2006/125958, WO 2006/112549, WO 2006/059163, WO2006/058923, WO 2006/049304, WO 2006/040529, WO 2006/040528, WO2006/016194, WO 2006/016178, WO 2006/016174, WO 2005/121110, WO2005/103021, WO 2005/095418, WO 2005/095417, WO 2005/090332, WO2005/080360, WO 2005/080359, WO 2005/066145, WO 2005/063738, WO2005/056530, WO 2005/054233, WO 2005/054200, WO 2005/049019, WO2005/046139, WO 2005/045614, WO 2005/044801, WO 2004/081001, WO2004/076420, WO 2004/072066, WO 2004/072031, WO 2004/063194, WO2004/063179, WO 2004/052869, WO 2004/050645, WO 2004/031179, WO2004/002481, WO 2003/095438, WO 2003/080585, WO 2003/055482, WO2003/047626, WO 2003/015774, WO 2003/000267, WO 2003/000262, WO2002/048106, WO 2002/046173, WO 2002/014312, WO 2002/008209, WO2001/085707, WO 2001/085706, WO 2001/083478, WO 2001/083465, WO2001/044216, and WO 2000/058293. The foregoing references are herebyincorporated by reference in their entireties.

Representative examples of glucokinase-activators are the compounds

wherein G₁ denotes cyclopropyl or cyclobutyl and G₂ denotes5-fluoro-thiazol-2-yl, 1-methyl-1H-pyrazol-3-yl, or pyrazin-2-yl; and

wherein G₃ denotes methyl or ethyl and G₄ denotes thiazol-2-yl,4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, or pyrazin-2-yl and thesalts thereof.

Examples of SGLT1 or SGLT2-inhibitors are described in WO 2006/108842,WO 2006/087997, WO 2006/080577, WO 2006/080421, WO 2006/073197, WO2006/064033, WO 2006/062224, WO 2006/054629, WO 2006/037537, WO2006/035796, WO 2006/018150, WO 2006/008038, WO 2006/002912, WO2006/010557, WO 2006/011502, WO 2006/011469, WO 2005/121161, WO2005/012326, WO 2005/095429, WO 2005/095372, WO 2005/095373, WO2005/092877, WO 2005/085267, WO 2005/085265, WO 2005/085237, WO2005/063785, WO 2005/021566, WO 2005/012243, WO 2005/012242, WO2005/012326, WO 2005/012318, WO 2005/011592, WO 2004/113359, WO2004/099230, WO 2004/089967, WO 2004/089966, WO 2004/087727, WO2004/080990, WO 2004/058790, WO 2004/052903, WO 2004/052902, WO2004/019958, WO 2004/018491, WO 2004/014932, WO 2004/014931, WO2004/013118, WO 2003/099836, WO 2003/080635, WO 2003/020737, WO2003/011880, WO 2003/000712, WO 2002/098893, WO 2002/088157, WO2002/083066, WO 2002/068440, WO 2002/068439, WO 2002/064606, WO2002/053573, WO 2002/044192, WO 2002/036602, WO 2002/028872, WO2001/074835, WO 2001/074834, WO 2001/068660, WO 2001/027128, WO2001/016147, JP 2005247834, JP 2004359630, JP 2004196788, JP 2003012686,and US 2006/063722. The foregoing references are hereby incorporated byreference in their entireties.

Representative examples of SGLT1 or SGLT2-inhibitors are the followingcompounds and the salts or complexes thereof with natural amino acids

wherein G₅ and G₈ independently of one another denote hydrogen,fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl,difluoromethyl, trifluoromethyl, ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl,hydroxy, methoxy, ethoxy, difluoromethoxy, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy or cyclohexyloxy; andG₆ denotes fluorine, chlorine, methyl, ethyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, trimethylsilylethyl, ethynyl,2-hydroxyprop-2-ylethynyl, 2-methoxyprop-2-ylethynyl,3-hydroxy-1-propyn-1-yl, 3-methoxy-1-propyn-1-yl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, tetra hydrofuran-3-yloxy, tetrahydropyran-4-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy andN-acetylpiperidin-4-yloxy; andG₇ denotes hydrogen or fluorine;

wherein G denotes fluorine, chlorine, methyl, ethyl, ethynyl, methoxy,ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy,cyclopentyloxy, 3-tetrahydrofuranyloxy, or 4-tetrahydropyranyloxy;

wherein G denotes fluorine, chlorine, methyl, ethyl, ethynyl, methoxy,ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy,cyclopentyloxy, 3-tetrahydrofuranyloxy, or 4-tetrahydropyranyloxy;

wherein G₈ denotes hydrogen, methoxycarbonyl, or ethoxycarbonyl and G₉denotes fluorine, chlorine, methyl, ethyl, ethynyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopentyloxy,3-tetrahydrofuranyloxy, or 4-tetrahydropyranyloxy; and

wherein:

-   G₁₀ denotes C₁₋₃-alkyl or perfluoro-C₁₋₃-alkyl;-   G₁₁ denotes hydrogen, C₁₋₃-alkyl or perfluoro-C₁₋₃-alkyl;-   G₁₂ denotes fluorine, chlorine, bromine, C₁₋₆-alkyl, C₁₋₆-alkyl    substituted by 1 to 3 fluorine atoms, C₁₋₆-alkoxy, C₁₋₆-alkoxy    substituted by 1 to 3 fluorine atoms, C₁₋₆-alkylthio, C₂₋₆-alkenyl,    C₂₋₆-alkynyl, perfluoro-C₁₋₃-alkyl, cyclobutyloxy, cyclopentyloxy,    cyclohexyloxy, tetrahydrofuranyloxy, or 4-tetrahydropyranyloxy; and-   G₁₃ and G₁₄ independently of one another denote hydrogen, fluorine,    chlorine, bromine, C₁₋₆-alkyl, C₁₋₆-alkyl substituted by 1 to 3    fluorine atoms, C₁₋₆-alkoxy, C₁₋₆-alkoxy substituted by 1 to 3    fluorine atoms, C₁₋₆-alkylthio, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    perfluoro-C₁₋₃-alkyl; and-   G₁₅ denotes hydrogen, C₂₋₂₀-alkanoyl, C₁₋₆-alkoxycarbonyl or    benzoyl.

A particularly preferred example of an antidiabetic combination partneris metformin in doses of about 100 mg to 500 mg or 200 mg to 850 mg (1-3times a day), or about 300 mg to 1000 mg once or twice a day, ordelayed-release metformin in doses of about 100 mg to 1000 mg orpreferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000mg once a day. Another particularly preferred example is pioglitazone ina dosage of about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day. Anotherparticularly preferred example is miglitol in a dosage of about 10 mg to50 mg or up to 100 mg 1-3 times a day.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin and rosuvastatin; fibrates such asbezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate andetofyllinclofibrate; nicotinic acid and the derivatives thereof such asacipimox; PPAR-alpha agonists; PPAR-delta agonists; inhibitors ofacyl-coenzyme A:cholesterolacyltransferase (ACAT; EC 2.3.1.26) such asavasimibe; cholesterol resorption inhibitors such as ezetimib;substances that bind to bile acid, such as cholestyramine, colestipoland colesevelam; inhibitors of bile acid transport; HDL modulatingactive substances such as D4F, reverse D4F, LXR modulating activesubstances and FXR modulating active substances; CETP inhibitors such astorcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO 2007/005572(anacetrapib); LDL receptor modulators; and ApoB100 antisense RNA. Aparticularly preferred example is atorvastatin in a dosage of about 1 mgto 40 mg or 10 mg to 80 mg once a day.

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretamide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan.Particularly preferred examples are metoprolol in a dosage of 50 mg to200 mg per day, Amlodipin in a dosage of 2.5 mg to 10 mg per day,ramipril in a dosage of 2.5 mg to 15 mg per day, valsartan in a dosageof 80 to 160 mg per day, and telmisartan in a dosage of 20 mg to 320 mgor 40 mg to 160 mg per day.

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat); alizyme; dexfenfluramine;axokine; cannabinoid receptor 1 antagonists such as the CB1 antagonistrimonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 aswell as NPY2 antagonists; beta3-AR agonists such as SB-418790 andAD-9677; 5HT2c receptor agonists such as APD 356; myostatin inhibitors;Acrp30 and adiponectin; steroyl CoA desaturase (SCD1) inhibitors; fattyacid synthase (FAS) inhibitors; CCK receptor agonists; Ghrelin receptormodulators; Pyy 3-36; orexin receptor antagonists; and tesofensine.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDLantibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1inhibitors.

Examples of combination partners for the treatment of heart failure arebeta-blockers such as atenolol, bisoprolol, celiprolol, and metoprolol;diuretics such as hydrochlorothiazide, chlortalidone, xipamide,furosemide, piretamide, torasemide, spironolactone, eplerenone,amiloride and triamterene; ACE inhibitors such as ramipril, lisinopril,cilazapril, quinapril, captopril, enalapril, benazepril, perindopril,fosinopril and trandolapril; as well as angiotensin II receptor blockers(ARBs) such as telmisartan, candesartan, valsartan, losartan,irbesartan, olmesartan and eprosartan; heart glycosides such as digoxinand digitoxin; combined alpha/beta-blockers such as carvedilol; B-typenatriuretic peptide (BNP) and BNP-derived peptides and BNP-fusionproducts. Particularly preferred examples are metoprolol in a dosage of50 mg to 200 mg per day, ramipril in a dosage of 2.5 mg to 15 mg perday, valsartan in a dosage of 80 to 160 mg per day, telmisartan in adosage of 20 mg to 320 mg or 40 mg to 160 mg per day, eplereron in adosage of 25-100 mg, digoxin in a dosage of 0.25 mg to 0.6 mg per daycarvedilol in a dosage of 3.25 mg to 100 mg, BNP (e.g. nesiritide) in adosage of 2 μg/kg as a bolus followed by 0.01 μg/kg/min.

Drug combinations comprising the selected DPP IV inhibitors contain forexample 1.75 mg to 10.5 mg glibenclamide, 500 mg to 3000 mg tolbutamide,0.5-6 g glimepiride, 2.5 mg to 40 mg glipizide, 1-4×30 mg gliquidone, to3×25 mg glibornuride, 80 mg to 160 mg gliclazide; 500 mg to 1000 mg,preferably 500 mg, 850 mg or 1000 mg metformin; 60 mg to 180 mgnateglinide; 0.25 mg to 4 mg repaglinide; 2 mg to 45 mgthiazolidinedione; 200 mg to 600 mg metaglidases; 2.5 mg to 5 mg PPARgamma/alpha modulators; 0.1 mg to 100 mg alpha glucosidase blocker;1-250 IU insulin; 15 μg to 120 μg Pramlintide; 5 mg to 80 mg statin; 50mg to 1000 mg fibrate; 1000 mg to 3000 mg nicotinic acid or derivative;about 250 mg acipimox; about 10 mg of a cholesterol resorptioninhibitor; 0.5 g to 30 g of a bile acid binding substance; 10 mg to 600mg and preferably 10 mg to 120 mg CETP inhibitor; 2.5 mg to 100 mgbeta-blocker; 3 mg to 200 mg diuretic; 2.5 mg to 500 mg calcium channelblocker; 1 mg to 40 mg ACE inhibitor; 5 mg to 600 mg angiotensin 11receptor blocker; 10 mg to 15 mg sibutramine; about 120 mg orlistat; 15mg to 30 mg dexfenfluramine; or 5 mg to 20 mg cannabinoid receptorantagonist, eplerenone in a dosage of 25 mg to 100 mg; digoxin in adosage of 0.25 mg to 0.6 mg per day; carvedilol in a dosage of 3.25 mgto 100 mg; BNP (e.g. nesiritide) in a dosage of 2 μg/kg as a bolusfollowed by 0.01 μg/kg/min.

EXAMPLES Example 1 Treatment of Pre-diabetes

The efficacy of a DPPIV inhibitor according to the invention in thetreatment of pre-diabetes characterised by pathological fasting glucoseand/or impaired glucose tolerance can be tested using clinical studies.In studies over a shorter period (e.g. 2-4 weeks) the success of thetreatment is examined by determining the fasting glucose values and/orthe glucose values after a meal or after a loading test (oral glucosetolerance test or food tolerance test after a defined meal) after theend of the period of therapy for the study and comparing them with thevalues before the start of the study and/or with those of a placebogroup. In addition, the fructosamine value can be determined before andafter therapy and compared with the initial value and/or the placebovalue. A significant drop in the fasting or non-fasting glucose levelsdemonstrates the efficacy of the treatment. In studies over a longerperiod (12 weeks or more) the success of the treatment is tested bydetermining the HbA1c value, by comparison with the initial value and/orwith the value of the placebo group. A significant change in the HbA1cvalue compared with the initial value and/or the placebo valuedemonstrates the efficacy of the DPP IV inhibitor for treatingpre-diabetes.

Example 2 Preventing Manifest Type 2 Diabetes

Treating patients with pathological fasting glucose and/or impairedglucose tolerance (pre-diabetes) is also in pursuit of the goal ofpreventing the transition to manifest type 2 diabetes. The efficacy of atreatment can be investigated in a comparative clinical study in whichpre-diabetes patients are treated over a lengthy period (e.g. 1-5 years)with either an active substance or a combination of active substances orwith placebo or with a non-drug therapy or other medicaments. During andat the end of the therapy, by determining the fasting glucose and/or aloading test (e.g. OGTT), a check is made to determine how many patientsexhibit manifest type 2 diabetes, i.e. a fasting glucose level of >125mg/dl and/or a 2 h value according to OGTT of >199 mg/dl. A significantreduction in the number of patients who exhibit manifest type 2 diabeteswhen treated with active substance or a combination of active substancesas compared to one of the other forms of treatment, demonstrates theefficacy of the active substance or combination of active substances inpreventing a transition from pre-diabetes to manifest diabetes.

Example 3 Treatment of Type 2 Diabetes

Treating patients with type 2 diabetes with the active substancesaccording to the invention, in addition to producing an acuteimprovement in the glucose metabolic situation, prevents a deteriorationin the metabolic situation in the long term. This can be observed ispatients are treated for a longer period, e.g. 1-6 years, with theactive substances or combinations of active substances according to theinvention and are compared with patients who have been treated withother antidiabetic medicaments. There is evidence of therapeutic successcompared with patients treated with other antidiabetic medicaments if noor only a slight increase in the fasting glucose and/or HbA1c value isobserved. Further evidence of therapeutic success is obtained if asignificantly smaller percentage of the patients treated with an activesubstance according to the invention or a combination of activesubstances according to the invention, compared with patients who havebeen treated with other medicaments, undergo a deterioration in theglucose metabolic position (e.g. an increase in the HbA1c value to >6.5%or >7%) to the point where treatment with an additional oralantidiabetic medicament or with insulin or with an insulin analogue orwith another antidiabetic agent (e.g. GLP-1 analogue) is indicated.

Example 4 Treatment of Insulin Resistance

In clinical studies running for different lengths of time (e.g. 2 weeksto 12 months) the success of the treatment is checked using ahyperinsulinaemic euglycaemic glucose clamp study. A significant rise inthe glucose infusion rate at the end of the study, compared with theinitial value or compared with a placebo group, or a group given adifferent therapy, proves the efficacy of an active substance orcombination of active substances in the treatment of insulin resistance.

Example 5 Treatment of Diabetic Hyper- or Dyslipidaemia

In clinical studies running for different lengths of time (e.g. 2 weeksto 60 months) on patients with type 2 diabetes the success of thetreatment is checked by determining the total cholesterol,LDL-cholesterol, HDL-cholesterol, and plasma triglycerides. Asignificant fall in the total cholesterol, LDL-cholesterol, or plasmatriglycerides and/or a rise in the HDL-cholesterol levels during or atthe end of the study, compared with the initial value or compared with aplacebo group, or a group given a different therapy, proves the efficacyof an active substance or combination of active substances in thetreatment of diabetic dys- or hyperlipidaemia.

Example 6 Treatment of Hyperglycaemia

In clinical studies running for different lengths of time (e.g. 1 day to24 months) the success of the treatment in patients with hyperglycaemiais checked by determining the fasting glucose or non-fasting glucose(e.g. after a meal or a loading test with oGTT or a defined meal). Asignificant fall in these glucose values during or at the end of thestudy, compared with the initial value or compared with a placebo group,or a group given a different therapy, proves the efficacy of an activesubstance or combination of active substances in the treatment ofhyperglycaemia.

Example 7 Treatment of Gestational Diabetes

In clinical studies running for a shorter period (e.g. 2-4 weeks) thesuccess of the treatment is checked by determining the fasting glucosevalues and/or the glucose values after a meal or after a loading test(oral glucose tolerance test or food tolerance test after a definedmeal) at the end of the therapeutic period of the study and comparingthem with the values before the start of the study and/or with those ofa placebo group. In addition, the fructosamine value can be determinedbefore and after treatment and compared with the initial value and/or aplacebo value. A significant fall in the fasting or non-fasting glucoselevels demonstrates the efficacy of an active substance or combinationof active substances.

In longer-running studies (12 weeks or more) the success of thetreatment is checked by determining the HbA1c value (compared withinitial value and placebo group). A significant change in the HbA1cvalue compared with the starting value and/or placebo value demonstratesthe efficacy of an active substance or combination of active substancesin the treatment of gestational diabetes.

Example 8 Treatment of Women who have had Gestational Diabetes

Patients with gestational diabetes have a significantly increased riskof contracting manifest type 2 diabetes after the pregnancy. Therapy maybe provided with the objective of preventing the transition to manifesttype 2. For this purpose, women with a history of gestational diabetesare treated either with an active substance according to the inventionor a combination of active substances according to the invention or withplacebo or with a non-drug therapy or with other medicaments, over alengthy period (e.g. 1-4 years). During and at the end of the treatmenta check is carried out by determining the fasting glucose and/or by aloading test (e.g. oGTT) to see how many patients have developedmanifest type 2 diabetes (fasting glucose level>125 mg/dl and/or 2 hvalue after oGTT>199 mg/dl). A significant reduction in the number ofpatients who develop manifest type 2 diabetes when treated with anactive substance according to the invention or a combination of activesubstances according to the invention, compared with a different type oftherapy, is proof of the efficacy of an active substance or acombination of active substances in preventing manifest diabetes inwomen with a history of gestational diabetes.

Example 9 Prevention of Micro- or Macrovascular Complications

The treatment of type 2 diabetes or pre-diabetes patients with an activesubstance according to the invention or a combination of activesubstances according to the invention prevents or reduces microvascularcomplications (e.g. diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, diabetic foot, diabetic ulcer) or macrovascularcomplications (e.g. myocardial infarct, acute coronary syndrome,unstable angina pectoris, stable angina pectoris, stroke, peripheralarterial occlusive disease, cardiomyopathy, heart failure, heart rhythmdisorders, vascular restenosis). Type 2 diabetes or patients withpre-diabetes are treated long-term, e.g. for 1-6 years, with an activesubstance according to the invention or a combination of activesubstances according to the invention and compared with patients whohave been treated with other antidiabetic medicaments or with placebo.Evidence of the therapeutic success compared with patients who have beentreated with other antidiabetic medicaments or with placebo can be foundin the smaller number of single or multiple complications. In the caseof macrovascular events, diabetic foot and/or diabetic ulcer, thenumbers are counted by anamnesis and various test methods. In the caseof diabetic retinopathy the success of the treatment is determined bycomputer-controlled illumination and evaluation of the background to theeye or other ophthalmic methods. In the case of diabetic neuropathy, inaddition to anamnesis and clinical examination, the nerve conductionrate can be measured using a calibrated tuning fork, for example. Withregard to diabetic nephropathy the following parameters may beinvestigated before the start, during and at the end of the study:secretion of albumin, creatinin clearance, serum creatinin values, timetaken for the serum creatinin values to double, time taken untildialysis becomes necessary.

Example 10 Treatment of Metabolic Syndrome

The efficacy of the active substances or combinations of activesubstances according to the invention can be tested in clinical studieswith varying run times (e.g. 12 weeks to 6 years) by determining thefasting glucose or non-fasting glucose (e.g. after a meal or a loadingtest with oGTT or a defined meal) or the HbA1c value. A significant fallin these glucose values or HbA1c values during or at the end of thestudy, compared with the initial value or compared with a placebo group,or a group given a different therapy, proves the efficacy of an activesubstance or combination of active substances in the treatment ofMetabolic Syndrome. Examples of this are a reduction in systolic and/ordiastolic blood pressure, a lowering of the plasma triglycerides, areduction in total or LDL cholesterol, an increase in HDL cholesterol ora reduction in weight, either compared with the starting value at thebeginning of the study or in comparison with a group of patients treatedwith placebo or a different therapy.

Example 11 DPPIV Inhibitor Film-coated Tablets

In order to prepare a granulating solution, copovidone is dissolved inpurified water at ambient temperature. DPP IV inhibitor, mannitol,pre-gelatinised starch and maize starch are mixed in a suitable mixer inorder to prepare a premix. The premix is moistened with the granulatingsolution and then granulated in a mixer with a high shear rate. Themoist granules are screened through a screen with a mesh size of 1.6 mm.The granules are dried at about 60° C. in a fluidised bed dryer until aloss in drying value of 2-4% is obtained. The finished mixture iscompressed to form tablet cores.

In a suitable mixer, hydroxypropylmethyl-cellulose, polyethyleneglycol,talc, titanium dioxide and iron oxide are suspended in purified water atambient temperature to prepare a suspension for the tablet coating. Thetablet cores are coated with this suspension until a weight increase of3% is obtained. For example, the following tablet compositions may beobtained in this way:

Ingredient mg mg mg mg mg DPP IV inhibitor 0.500 1.000 2.500 5.00010.000 mannitol 67.450 66.950 65.450 130.900 125.900 pre-gelatinisedstarch 9.000 9.000 9.000 18.000 18.000 maize starch 9.000 9.000 9.00018.000 18.000 copovidone 2.700 2.700 2.700 5.400 5.400 magnesiumstearate 1.350 1.350 1.350 2.700 2.700 Total mass 90.000 90.000 90.000180.000 180.000 (tablet core) HPMC 1.500 1.500 1.500 2.500 2.500 PEG0.150 0.150 0.150 0.250 0.250 titanium dioxide 0.750 0.750 0.750 1.2501.250 talc 0.525 0.525 0.525 0.875 0.875 iron oxide, yellow 0.075 0.0750.075 0.125 0.125 Total mass 93.000 93.000 93.000 185.000 185.000(film-coated tablet)

Example 12 Enhancing the Vitality and Secretion Capacity of Islets ofLangerhans or Beta Cells

This is done after successful isolation of the islets of Langerhans orpancreatic beta cells, by storing them, transporting them or cultivatingthem in a medium which contains DPP IV inhibitors in a concentration of1 nmol/l to 1 μmol/l, preferably in a concentration of 1 nmol/l and 100nmol/l, for future transplantation.

In addition, after transplantation with islets of Langerhans orpancreatic beta cells, the patients (and these may also be animals) aretreated with DPP IV inhibitors in a daily dosage of between 1 mg and 200mg, preferably with a dose of 5 mg and 100 mg of a DPP IV inhibitor, inorder to enhance the vitality and secretion capacity of the transplant.This is tested either by analysis of the insulin secretion afterstimulation with glucose or another agent that increases insulinsecretion. Moreover, the improvement in the quality may also be checkedin vitro or in animal models using the TUNEL technique, which isdescribed in Diabetologia 42:566, 1999 or Diabetes 48:738, 1999(investigation of apoptosis and inhibition thereof).

Example 13 Combined Treatment with DPP IV Inhibitor—Metformin

For treating type 2 diabetes or pre-diabetes a DPP IV inhibitoraccording to the invention may be combined with the anti-diabeticallyactive substance metformin, either in a free combination or in a fixedcombination in a tablet. A therapeutically effective dose of the DPP IVinhibitor (e.g. a dose of between 0.1 and 100 mg) may be combined withdifferent doses of metformin, e.g. with 500 mg, 850 mg or 1000 mgmetformin as a single dose with a total daily dose of metformin of500-2850 mg, or with 500 mg, 1000 mg, 1500 mg, or 2000 mg metformin indelayed-release form. The clinical efficacy of such a combination withmetformin can be tested in a clinical study. For this, patients withtype 2 diabetes or with pre-diabetes are treated either with a DPP IVinhibitor on its own or with metformin on its own or with a combinationvon DPP IV inhibitor and metformin. The treatment lasts between 2 weeksand 6 years. Evidence that the combination is appropriate and effectivecan be found in the fact that the combination of a DPP-IV inhibitor withmetformin leads to a significantly greater reduction in the fastingglucose and/or non-fasting glucose and/or the HbA1c value than eitherthe DPP IV inhibitor alone or metformin alone.

Example 14 Combined Treatment with DPP IV Inhibitor—Glitazone

For treating type 2 diabetes or pre-diabetes a DPP IV inhibitoraccording to the invention may be combined with the anti-diabeticallyactive substance group comprising the glitazones or thiazolidinediones(e.g. pioglitazone or rosiglitazone), either in a free combination or ina fixed combination in a tablet. A therapeutically effective dose of theDPP IV inhibitor (e.g. a dose of between 0.1 and 100 mg) may be combinedwith different doses of pioglitazone (15 mg, 30 mg, or 45 mg) orrosiglitazone (2 mg, 4 mg or 8 mg, given either once or twice a day).The clinical efficacy of such a combination with rosiglitazone orpioglitazone can be tested in a clinical study. For this, patients withtype 2 diabetes or with pre-diabetes are treated either with a DPP IVinhibitor on its own or with rosiglitazone or pioglitazone alone or witha combination of DPP IV inhibitor and rosiglitazone or pioglitazone. Thetreatment lasts between 2 weeks and 6 years. Evidence that thecombination is appropriate and effective can be found in the fact thatthe combination of a DPP-IV inhibitor with rosiglitazone or pioglitazoneleads to a significantly greater reduction in the fasting glucose and/ornon-fasting glucose and/or the HbA1c value than either the DPP IVinhibitor alone or rosiglitazone or pioglitazone alone.

Example 15 Combined Treatment with DPP IV Inhibitor—SGLT2 Inhibitor

For treating type 2 diabetes or pre-diabetes a DPP IV inhibitoraccording to the invention may be combined with the anti-diabeticallyactive substance group comprising the SGLT-2 inhibitors, either in afree combination or in a fixed combination in a tablet. Atherapeutically effective dose of the DPP IV inhibitor (e.g. a dose ofbetween 0.1 and 100 mg) may be combined with different doses of SGLT-2inhibitor (0.5 mg to 1000 mg). The clinical efficacy of such acombination with SGLT-2 inhibitor can be tested in a clinical study. Forthis, patients with type 2 diabetes or with pre-diabetes are treatedeither with a DPP IV inhibitor on its own or with a SGLT-2 inhibitor onits own or with a combination of DPP IV inhibitor and SGLT-2 inhibitor.The treatment lasts between 2 weeks and 6 years. Evidence that thecombination is appropriate and effective can be found in the fact thatthe combination of a DPP-IV inhibitor with the SGLT-2 inhibitor leads toa significantly greater reduction in the fasting glucose and/ornon-fasting glucose and/or the HbA1c value than either the DPP IVinhibitor alone or the SGLT-2 inhibitor alone.

Example 16 Combined Treatment with DPP IV Inhibitor—Antihypertensive

For treating a patient with type 2 diabetes or pre-diabetes or withMetabolic Syndrome a DPP IV inhibitor according to the invention may becombined with an anti-hypertensively active substance, either in a freecombination or in a fixed combination in a tablet. A therapeuticallyeffective dose of the DPP IV inhibitor (e.g. a dose of between 0.1 and100 mg) may be combined with different doses of ACE-inhibitors (e.g. 2.5mg to 15 mg ramipril), AT1-receptor-antagonists (e.g. 20 mg to 160 mgtelmisartan), beta-blockers (e.g. 50 mg to 200 mg metoprolol), ordiuretics (e.g. 12.5 mg to 25 mg hydrochlorothiazide). The clinicalefficacy of such a combination with antihypertensives can be tested in aclinical study. For this, patients with type 2 diabetes or withpre-diabetes or with Metabolic Syndrome are treated either with a DPP IVinhibitor on its own or with an antihypertensive on its own or with acombination of DPP IV inhibitor and antihypertensive. The treatmentlasts between 2 weeks and 6 years. Evidence that the combination isappropriate and effective can be found in the fact that the combinationof a DPP-IV inhibitor with the antihypertensive lowers the fastingglucose and/or non-fasting glucose and/or the HbA1c value at least asmuch as the DPP IV inhibitor alone, and if the combination of the DPP-IVinhibitor with the antihypertensive lowers the systolic and/or diastolicarterial blood pressure at least as much as the antihypertensive alone.

Example 17 Combined Treatment with DPP IV Inhibitor—Lipid Lowering Agent

For treating a patient with type 2 diabetes or pre-diabetes or withMetabolic Syndrome or with diabetic dys- or hyperlipidaemia, a DPP IVinhibitor according to the invention may be combined with a lipidlowering agent/HDL-raising agent, either in a free combination or in afixed combination in a tablet. A therapeutically effective dose of theDPP IV inhibitor (e.g. a dose of between 0.1 and 100 mg) may be combinedwith different doses of statins (e.g. 10 mg to 80 mg atorvastatin or 10mg to 80 mg simvastatin), fibrates (e.g. fenofibrate), cholesterolabsorption inhibitors, or with HDL-raising substances such asCETP-inhibitors (e.g. torcetrapib 10 mg to 120 mg once a day or 120 mgtwice a day). The clinical efficacy of such a combination with lipidlowering agents/HDL-raising agents can be tested in a clinical study.For this, patients with type 2 diabetes or with pre-diabetes or withMetabolic Syndrome or with diabetic dys- or hyperlipidaemia are treatedeither with a DPP IV inhibitor on its own or with a lipid loweringagent/HDL-raising agent on its own or with a combination of DPP IVinhibitor and lipid lowering agent/HDL-raising agent. The treatmentlasts between 2 weeks and 6 years. Evidence that the combination isappropriate and effective can be found in the fact that the combinationof the DPP-IV inhibitor with the lipid lowering agent/HDL-raising agentlowers the fasting glucose and/or non-fasting glucose and/or the HbA1cvalue at least as much as the DPP IV inhibitor alone, and if thecombination of the DPP-IV inhibitor with a lipid loweringagent/HDL-raising agent lowers the total cholesterol or LDL-cholesterolor plasma triglycerides at least as much or increases theHDL-cholesterol value at least as much as the lipid loweringagent/HDL-raising agent alone.

Example 18 Combined Treatment of DPP IV Inhibitor—BNP/BNP-DerivedPeptides or BNP-Fusion Peptides in Patients with Heart Failure

For treating a patient with acute heart failure, a DPP IV inhibitoraccording to the invention may be combined with a substance thatfavourably affects heart failure, either in a free combination or in afixed combination in a tablet. A therapeutically effective dose of theDPP IV inhibitor (e.g. a dose of between 0.1 and 100 mg) may be combinedwith different doses of ACE-inhibitors (e.g. 2.5 mg to 15 mg ramipril),AT1-receptor-antagonists (e.g. 20 mg to 160 mg telmisartan),beta-blockers (e.g. 50 mg to 200 mg metoprolol), combinedalpha/beta-blockers (e.g. 3.25 mg to 100 mg carvedilol), diuretics (e.g.12.5 mg to 25 mg hydrochlorothiazide), mineralocorticoid receptorantagonists (e.g. 25 mg to 100 mg eplerenone; and/or B-type natriureticpeptide (BNP) (e.g. 2 μg/kg as a bolus followed by 0.01 μg/kg/minnesiritide), a BNP-derived peptide or a BNP-fusion product. Thecombination of BNP and DPP-IV inhibitor leads to a higher concentrationof full length BNP (1-32) in vivo. The clinical efficacy of thecombinations specified can be tested in clinical studies. The treatmentlasts between 1 day and 6 years. Evidence that the combination iseffective in treating acute heart failure can be found in the fact thatcompared with other therapies the combination leads to a significantimprovement in the clinical situation (higher cardiac ejection outputand/or reversal of pulmonary congestion, and/or reversal of pulmonarywedge pressure, and/or a reduction in mortality caused by acute heartfailure).

Example 19 Treatment with DPP-IV Inhibitor in Patients with HeartFailure

A DPP IV inhibitor according to the invention may be used to treat apatient with chronic heart failure. This treatment leads to a higherconcentration of endogenous full length BNP (1-32) in vivo. The clinicalefficacy of this treatment is tested in clinical studies. The treatmentlasts between 2 weeks and 6 years. Evidence that the combination iseffective in treating chronic heart failure can be found in the factthat a DPP-IV inhibitor according to the invention leads to asignificant improvement in the clinical situation compared with adifferent treatment or placebo (less frequent hospitalisation due toacute heart failure, the ability to walk longer distances, a higherloadability in ergometrics, a higher cardiac ejection output and/orreversal of pulmonary congestion, and/or a reduction in mortality causedby heart failure).

1. A method of reducing the risk of a macrovascular complication in thetreatment of patients who have been diagnosed with manifest type 2diabetes comprising the steps of preparing an oral medicament comprising1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine or one of the salts thereof, and administering said oralmedicament to said patient, wherein the oral medicament is a tablet andthe amount of said 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine administered to said patient is 0.5 mg, 1 mg, 2.5 mg, 5 mg, or10 mg, and wherein the macrovascular complication is myocardialinfarction, acute coronary syndrome, unstable angina pectoris, stableangina pectoris, haemorrhagic or ischaemic stroke, peripheral arterialocclusive disease, cardiomyopathy, left heart insufficiency, right heartinsufficiency, global heart failure, heart rhythm disorders, or vascularrestenosis.
 2. The method of claim 1, wherein the medicament furthercomprises an active substance selected from: metformin, pioglitazone,miglitol, atorvastatin, valsartan and telmisartan.
 3. The method ofclaim 1, wherein the medicament further comprises metformin.
 4. Themethod of claim 1, wherein the medicament further comprisespioglitazone.
 5. A method of treating a patient who has been diagnosedwith manifest type 2 diabetes comprising administering to the patient anoral medicament in the form of a tablet comprising1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineor one of the salts thereof, wherein the amount of said1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineadministered to said patient is 0.5 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg,and wherein the risk of a macrovascular complication is reduced by usingthe medicament, and wherein the macrovascular complication is myocardialinfarction, acute coronary syndrome, unstable angina pectoris, stableangina pectoris, haemorrhagic or ischaemic stroke, peripheral arterialocclusive disease, cardiomyopathy, left heart insufficiency, right heartinsufficiency, global heart failure, heart rhythm disorders, or vascularrestenosis.
 6. The method of claim 1 wherein the oral medicament furthercomprises telmisartan.
 7. The method of claim 5 further comprisingadministering an active substance selected from metformin, pioglitazone,miglitol, atorvastatin, valsartan and telmisartan.
 8. The method ofclaim 5 further comprising administering metformin.
 9. The method ofclaim 5 further comprising administering pioglitazone.
 10. The method ofclaim 5 further comprising administering telmisartan.
 11. The method ofclaim 1, wherein the amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineadministered to said patient is a daily dose of 5 mg.
 12. The method ofclaim 5, wherein the amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine administered to saidpatient is a daily dose of 5 mg.
 13. The method of claim 1, wherein theamount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineadministered to said patient is 2.5 mg or 5 mg.
 14. The method of claim5, wherein the amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineadministered to said patient is 2.5 mg or 5 mg.
 15. The method of claim3 wherein metformin is comprised in an amount of about 500 mg, 850 mg,or 1000 mg.
 16. The method of claim 3 wherein metformin is comprised indelayed-release form in an amount of about 500 mg, 1000 mg, 1500 mg, or2000 mg.
 17. The method of claim 4 wherein pioglitazone is comprised inan amount of about 15 mg, 30 mg, or 45 mg.
 18. The method of claim 6wherein telmisartan is comprised in an amount from about 20 mg to about160 mg.
 19. The method of claim 5 further comprising administering anactive substance selected from: metformin; sulphonylureas selected fromglibenclamide, tolbutamide, glimepiride, glipizide, gliquidon,glibornuride and gliclazide; nateglinide; repaglinide;thiazolidinediones selected from rosiglitazone and pioglitazone;alpha-glucosidase blockers selected from acarbose, voglibose andmiglitol; insulin and insulin analogues selected from human insulin,insulin lispro, insulin glusilin, r-DNA-insulinaspart, NPH insulin,insulin detemir, insulin zinc suspension and insulin glargin; and GLP-1and GLP-1 analogues selected from Exendin
 4. 20. The method of claim 8wherein the amount of metformin is about 500 mg, 850 mg, or 1000 mg. 21.The method of claim 8 wherein the amount of metformin is about 500 mg,1000 mg, 1500 mg, or 2000 mg, each in delayed-release form.
 22. Themethod of claim 9 wherein the amount of pioglitazone is about 15 mg, 30mg, or 45 mg.
 23. The method of claim 10 wherein the amount oftelmisartan is from about 20 mg to about 160 mg.
 24. A method ofreducing the risk of a macrovascular complication in the treatment ofpatients who have been diagnosed with manifest type 2 diabetescomprising administering to a patient in need thereof an oral medicamentin the form of a tablet comprising1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl -7-(2-butyn-1-yl)8-(3-(R)-amino-piperidin-1-yl)-xanthine in an amount of 2.5 mg or 5 mg,wherein the macrovascular complication is myocardial infarction, acutecoronary syndrome, unstable angina pectoris, stable angina pectoris,haemorrhagic or ischaemic stroke, peripheral arterial occlusive disease,cardiomyopathy, left heart insufficiency, right heart insufficiency,global heart failure, heart rhythm disorders, or vascular restenosis.25. The method of claim 24, wherein the medicament further comprisesmetformin.
 26. The method of claim 24, wherein the medicament furthercomprises pioglitazone.
 27. The method of claim 24, wherein themedicament further comprises telmisartan.
 28. The method of claim 25wherein metformin is comprised in an amount of about 500 mg, 850 mg, or1000 mg.
 29. The method of claim 26 wherein pioglitazone is comprised inan amount of about 15 mg, 30 mg, or 45 mg.
 30. The method of claim 27wherein telmisartan is comprised in an amount of about 20 mg to about160 mg.
 31. The method of claim 25 wherein metformin is comprised indelayed-release form in an amount of about 500 mg, 1000 mg, 1500 mg, or2000 mg.
 32. A method of reducing the risk of a macrovascularcomplication in the treatment of patients who have been diagnosed withmanifest type 2 diabetes comprising administering to a patient in needthereof an oral medicament in the form of a tablet comprising1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine in an amount of 5 mg, whereinthe macrovascular complication is myocardial infarction, acute coronarysyndrome, unstable angina pectoris, stable angina pectoris, haemorrhagicor ischaemic stroke, peripheral arterial occlusive disease,cardiomyopathy, left heart insufficiency, right heart insufficiency,global heart failure, heart rhythm disorders, or vascular restenosis.33. The method of claim 32 further comprising administering an activesubstance selected from, metformin; sulphonylureas selected fromglibenclamide, tolbutamide, glimepiride, glipizide, gliquidon,glibornuride and gliclazide; nateglinide; repaglinide;thiazolidinediones selected from rosiglitazone and pioglitazone;alpha-glucosidase blockers selected from acarbose, voglibose andmiglitol; insulin and insulin analogues selected from human insulin,insulin lispro, insulin glusilin, r-DNA-insulinaspart, NPH insulin,insulin detemir, insulin zinc suspension and insulin glargin; and GLP-1and GLP-1 analogues selected from Exendin
 4. 34. The method of claim 32further comprising administering an active substance selected from: ACEinhibitors selected from ramipril, lisinopril, cilazapril, quinapril,captopril, enalapril, benazepril, perindopril, fosinopril andtrandolapril; angiotensin II receptor blockers (ARBs) selected fromtelmisartan, candesartan, valsartan, losartan, irbesartan, olmesartanand eprosartan; beta blockers selected from atenolol, bisoprolol,celiprolol, carvedilol, and metoprolol; and diuretics selected fromhydrochlorothiazide, chlortalidone, xipamide, furosemide, piretanide,torasemide, spironolactone, eplerenone, amiloride and triamterene. 35.The method of claim 32 further comprising administering an activesubstance selected from: statins selected from simvastatin,atorvastatin, lovastatin, fluvastatin, pravastatin and rosuvastatin;fibrates selected from bezafibrate, fenofibrate, clofibrate,gemfibrozil, etofibrate and etofyllinclofibrate; cholesterol absorptioninhibitors selected from ezetimib; and HDL-raising substances selectedfrom torcetrapib, dalcetrapib and anacetrapib.
 36. The method of claim32 further comprising administering an active substance selected frommetformin, pioglitazone, miglitol, atorvastatin, valsartan andtelmisartan.
 37. The method of claim 32 further comprising administeringmetformin.
 38. The method of claim 32 further comprising administeringpioglitazone.
 39. The method of claim 32 further comprisingadministering telmisartan.
 40. A method of reducing the risk of amacrovascular complication in the treatment of patients who have beendiagnosed with manifest type 2 diabetes comprising administering to apatient in need thereof an oral medicament in the form of a tabletcomprising1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, wherein the macrovascularcomplication is myocardial infarction, acute coronary syndrome, unstableangina pectoris, stable angina pectoris, haemorrhagic or ischaemicstroke, peripheral arterial occlusive disease, cardiomyopathy, leftheart insufficiency, right heart insufficiency, global heart failure,heart rhythm disorders, or vascular restenosis, and wherein the totaldaily dose of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineadministered is 5 mg.
 41. The method of claim 40 further comprisingadministering an active substance selected from: metformin;sulphonylureas selected from glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinid; thiazolidinediones selected from rosiglitazone andpioglitazone; alpha-glucosidase blockers selected from acarbose,voglibose and miglitol; insulin and insulin analogues selected fromhuman insulin, insulin lispro, insulin glusilin, r-DNA-insulinaspart,NPH insulin, insulin detemir, insulin zinc suspension and insulinglargin; and GLP-1 and GLP-1 analogues selected from Exendin
 4. 42. Themethod of claim 40 further comprising administering an active substanceselected from: ACE inhibitors selected from ramipril, lisinopril,cilazapril, quinapril, captopril, enalapril, benazepril, perindopril,fosinopril and trandolapril; angiotensin II receptor blockers (ARBs)selected from telmisartan, candesartan, valsartan, losartan, irbesartan,olmesartan and eprosartan; beta blockers selected from atenolol,bisoprolol, celiprolol, carvedilol, and metoprolol; and diureticsselected from hydrochlorothiazide, chlortalidone, xipamide, furosemide,piretanide, torasemide, spironolactone, eplerenone, amiloride andtriamterene.
 43. The method of claim 40 further comprising administeringan active substance selected from: statins selected from simvastatin,atorvastatin, lovastatin, fluvastatin, pravastatin and rosuvastatin;fibrates selected from bezafibrate, fenofibrate, clofibrate,gemfibrozil, etofibrate and etofyllinclofibrate; cholesterol absorptioninhibitors selected from ezetimib; and HDL-raising substances selectedfrom torcetrapib, dalcetrapib and anacetrapib.
 44. The method of claim40 further comprising administering an active substance selected frommetformin, pioglitazone, miglitol, atorvastatin, valsartan andtelmisartan.
 45. The method of claim 40 further comprising administeringmetformin.
 46. The method of claim 40 further comprising administeringpioglitazone.
 47. The method of claim 40 further comprisingadministering telmisartan.